- Synthesis of 4-azachromeno[2,3-b]indol-11(6H)-one and its derivatives as analogues of ellipticine
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4-Azachromeno[2,3-b]indol-11(6H)-ones (4) and their derivatives (5) as analogues of ellipticine were synthesized through a straightforward, two or three-step process. Tetracyclic heterocycles (4) were obtained by facile cyclization of indolin-2-ones (2) or (3) and 2-chloronicotinoyl chloride under the condition of the 'Jensen'-reaction. Alkylation of the compounds (4) afforded 6-substituted 4-azachromeno[2,3-b]indol-ll(6H)-ones.
- Chen, Yanhong,Yang, Chunhao,Xie, Yuyuan
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Read Online
- Synthesis of oxindole from acetanilide via Ir(iii)-catalyzed C-H carbenoid functionalization
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Herein we disclose the first report on the synthesis of oxindole derivatives from acetanilide via Ir(iii)-catalyzed intermolecular C-H functionalization with diazotized Meldrum's acid. A broad range of substituted anilides were found to react smoothly under the Ir(iii)-catalytic system to afford the corresponding N-protected oxindoles. The N-protecting groups, such as Ac, Bz or Piv, can be easily removed to furnish the oxindole. Various synthetic applications of the synthesized oxindole were also demonstrated.
- Patel, Pitambar,Borah, Gongutri
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p. 443 - 446
(2017/01/03)
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- Discovery of a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth
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Despite recent advances in molecularly directed therapy, triple negative breast cancer (TNBC) remains one of the most aggressive forms of breast cancer, still without a suitable target for specific inhibitors. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC, where level of overexpression correlates with poor prognosis and an aggressive disease course. Herein, we describe the discovery through targeted kinase inhibitor library screening, and structure-guided design of a series of ATP-competitive indolinone derivatives with subnanomolar inhibition constants towards MELK. The most potent compound, 17, inhibits the expression of the anti-apoptotic protein Mcl-1 and proliferation of TNBC cells exhibiting selectivity for cells expressing high levels of MELK. These studies suggest that further elaboration of 17 will furnish MELK-selective inhibitors with potential for development in preclinical models of TNBC and other cancers.
- Edupuganti, Ramakrishna,Taliaferro, Juliana M.,Wang, Qiantao,Xie, Xuemei,Cho, Eun Jeong,Vidhu, Fnu,Ren, Pengyu,Anslyn, Eric V.,Bartholomeusz, Chandra,Dalby, Kevin N.
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p. 2609 - 2616
(2017/04/06)
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- COMPOUND; TAUTOMER AND GEOMETRIC ISOMER THEREOF; SALT OF SAID COMPOUND, TAUTOMER, OR GEOMETRIC ISOMER; METHOD FOR MANUFACTURING SAID COMPOUND, TAUTOMER, ISOMER, OR SALT; ANTIMICROBIAL AGENT; AND ANTI-INFECTIVE DRUG
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A compound represented by any one of General Formulas (1) to (5), a tautomer or geometric isomer thereof, or a salt thereof.
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Paragraph 0167-0168; 0169
(2015/09/23)
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- General synthesis of mono-, di-, and tri-acetylated indoles from indolin-2-ones
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Having developed the one-pot triacetylation of indolin-3-ones, we have now devised a simple two-step reaction sequences to produce di- and mono-acetylated indoles from indolin-2-ones. The indolin-2-ones were first subjected to acetylation in the presence of acetic anhydride and a catalytic amount of N,N-dimethylaminopyridine to give 2-acetoxy-1,3-diacetylindoles. Subsequently, an enzyme-assisted deacetylation resulted in the chemoselective deprotection of the acetoxy group to produce 1,3-diacetyl-2-hydroxyindoles. However, a chemical deacetylation of 2-acetoxy-1,3-diacetylinoles under mild basic or acidic conditions resulted in the formation of 3-acetyl-2-hydroxyindoles.
- Jha, Mukund,Chou, Ting-Yi,Blunt, Brian
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experimental part
p. 982 - 989
(2011/03/19)
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- Inhibitors of the salicylate synthase (Mbti) from Mycobacterium tuberculosis discovered by high-throughput screening
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A simple steady-state kinetic high-throughput assay was developed for the salicylate synthase MbtI from Mycobacterium tuberculosis, which catalyzes the first committed step of mycobactin biosynthesis. The mycobactins are small-molecule iron chelators produced by M. tuberculosis, and their biosynthesis has been identified as a promising target for the development of new antitubercular agents. The assay was miniaturized to a 384-well plate format and high-throughput screening was performed at the National Screening Laboratory for the Regional Centers of Excellence in Biodefense and Emerging Infectious Diseases (NSRB). Three classes of compounds were identified comprising the benzisothiazolones (class I), diarylsulfones (class II), and benzimidazole-2-thiones (class III). Each of these compound series was further pursued to investigate their biochemical mechanism and structure-activity relationships. Benzimidazole-2-thione 4 emerged as the most promising inhibitor owing to its potent reversible inhibition.
- Vasan, Mahalakshmi,Neres, Joao,Williams, Jessica,Wilson, Daniel J.,Teitelbaum, Aaron M.,Remmel, Rory P.,Aldrich, Courtney C.
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experimental part
p. 2079 - 2087
(2011/11/29)
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- NOVEL HYDROXYINDOLE DERIVATIVE
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A compound or a pharmaceutically acceptable salt thereof of the present invention is represented by the following general formula (I): [wherein, R1 to R8 may have a hydrogen atom, a halogen atom, a hydroxy group, a C1-C6 alkyl group,
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Page/Page column 18
(2009/12/24)
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- Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120)
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Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a newtreatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.
- Roth, Gerald J.,Heckel, Armin,Colbatzky, Florian,Handschuh, Sandra,Kley, J?rg,Lehmann-Lintz, Thorsten,Lotz, Ralf,Tontsch-Grunt, Ulrike,Walter, Rainer,Hilberg, Frank
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experimental part
p. 4466 - 4480
(2010/03/02)
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- N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
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The present invention provides novel ureas containing N-aryl or N-heteroaryl substituted heterocycles of Formula (I): or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, B, D and W are as defined herein. These compounds are selective inhibitors of the human P2Y1 receptor which can be used as medicaments.
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Page/Page column 71
(2010/11/25)
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- Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
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The present invention provides novel ureas containing N-aryl or N-heteroaryl substituted heterocycles and analogues thereof, which are selective inhibitors of the human P2Y1 receptor. The invention also provides for various pharmaceutical compositions of the same and methods for treating diseases responsive to modulation of P2Y1 receptor activity.
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Page/Page column 52
(2008/06/13)
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- Concise syntheses of the cruciferous phytoalexins brassilexin, sinalexin, wasalexins, and analogues: Expanding the scope of the Vilsmeier formylation
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(Chemical Equation Presented) Efficient syntheses of the phytoalexins brassilexin, sinalexin, and analogues are demonstrated through the application of the Vilsmeier formylation to indoline-2-thiones followed by a new aqueous ammonia workup procedure. Similarly, a very concise two-pot synthesis of the phytoalexins wasalexins using sequential formylation-amination of indolin-2-ones is described. Remarkably, this novel aqueous ammonia workup allows the sequential one-pot formylation-amination, expanding substantially the scope of the Vilsmeier formylation of both indoline-2-thiones and indolin-2-ones. The examination of the formylation-amination reaction and optimization of conditions, as well as the syntheses and antifungal activities of several brassilexin analogues, are reported.
- Pedras, M. Soledade C.,Jha, Mukund
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p. 1828 - 1834
(2007/10/03)
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- HETEROCYCLICALLY SUBSTITUTED INDOLINONES, THEIR PRODUCTION AND USE AS MEDICAMENTS
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The invention relates to heterocyclically substituted indolinones of general formula (I), in which R1 to R5 and X are defined as cited in claim 1, to their tautomers, diastereomers, enantiomers and to their mixtures, prodrugs and salts, in particular their physiologically compatible salts. Said compounds exhibit valuable pharmacological characteristics, in particular an inhibiting action on various receptor tyrosine kinases and cyclin-CDK complexes and on the proliferation of endothelial cells and various tumour cells. The invention also relates to medicaments containing said compounds, to the use of the latter and to a method for producing the same.
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Page/Page column 81
(2008/06/13)
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- Substituted indolinones, preparation thereof and their use as pharmaceutical compositions
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Indolinones of general formula I which are inhibitors of cell proliferation, particularly of tumour cells, and inhibitors of protein kinases. The following compounds are exemplary: (Z)-3-{1-[4-(N-(2-aminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone, (Z)-3-{1 -[4-(N-(2-dimethylaminoethyl)-N-phenylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone, and (Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone.
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- Studies on protection of oxindoles
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Protection of amide nitrogen of oxindole and methyloxindole using Boc and Z-groups has been described. Sodium carbonate was found to be an effective base for these protections.
- Rajeswaran, Walajapet G.,Cohen, Louis A.
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p. 11375 - 11380
(2007/10/03)
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- Synthesis and aldose reductase inhibitory activity of substituted 2(1H)-benzimidazolone- and oxindole-1-acetic acids
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Potent in vitro inhibition of the enzyme aldose reductase (AR) was observed with several members of a series of 3-alkylated 2(1H)-benzimidazolone-1-acetic acids, as well as with analogs from a structurally-related series of oxindole-1-acetic acids with 3-alkyl or 3-alkylidene substituents.Intrinsic activity against AR was, in general, greatest in compounds from the second series, especially with analogs which containalkylidene side chains, with typical IC50 values of 1 μM.However, in streptozotocindiabetic rat model, the best compounds from either series failedto prevent sorbitol accumulation in lens or sciatic nerve to the degree observed with AR inhibitors such as ponalrestat or zopolrestat. aldose reductase / diabetes / 2(1H)-benzimidazolone-1-acetic acid / oxindole-1-acetic acid
- Howard, HR,Sarges, R,Siegel, TW,Beyer, TA
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p. 779 - 789
(2007/10/02)
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- Heterocyclic Aromatic Anions with 4n + 2 ?-Electrons
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Equilibrium acidities in DMSO for several cyclic carboxamides, thiocarboxamides, esters, and sulfones that form anions possessing 4n + 2 electrons have been measured.Aromatic stabilization energies (ASEs) for these anions have been estimated by comparing
- Bordwell, Frederick G.,Fried, Herbert E.
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p. 4218 - 4223
(2007/10/02)
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- Oxidation of Indoles with Oxodiperoxomolybdenum (VI), MoO5*HMPA. Preparation of 2-Hydroxyindoxyl and Isatogen Derivatives
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Oxidation of 1-acetylindoles 1 with (hexamethylphosphoramide)oxodiperoxomolybdenum(VI), MoO5*HMPA, in dry methylene chloride gave 1-acetyl-2-hydroxyindoxyls 4. 2-Phenylindole (8) was similarly treated with MoO5*HMPA to give a dimeric product 11, while oxi
- Chien, Chung-Sheng,Takanami, Toshikatsu,Kawasaki, Tomomi,Sakamoto, Masanori
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p. 1843 - 1848
(2007/10/02)
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